Patent EA-003427-B1 (EA)
Title: An iron-dextran compound for use as a component in a therapeutical composition for prophylaxis or treatment of iron-deficiency, a process for producing said iron-dextran compound and use of said compound for the preparation of a parenterally administrable therapeutical composition
Inventor: ANDREASEN HANS
IPC: A61K47/48
Filed: 1999-03-24
Abstract: 1. An iron-dextran compound for use in producing a therapeutical composition for prophylaxis or treatment of iron-deficiency in an animal or human and suitable for parenteral administration, comprising a hydrogenated dextran having a weight average molecular weight (Mw) of 700-1,400 Daltons, preferably about 1,000 Daltons, and a number average molecular weight (Mn) of 400-1,400 Daltons, wherein 90% by weight of the dextran has a molecular weight of less than 2,700 Daltons and the Mw of the 10% by weight fraction of the dextran having the highest molecular weights is below 3,200 Daltons, said hydrogenated dextran having been subjected to purification by membrane processes having a cut-off value of 340-800 Daltons, in stable association with ferric oxyhydroxide. 2. A process for producing the iron-dextran compound of claim 3, in which the molecular weight of dextran is reduced by hydrolysis and the dextran is hydrogenated to convert functional aldehyde terminal groups into alcohol groups; the hydronated dextran as an aqueous solution is combined with at least one water sosuable ferric salt; base is added to the resulting solution to form ferric hydroxide, and the resulting mixture is heated to transform the ferric hydroxide into ferric oxyhydroxide in association with the dextran, characterized in that after said hydrolyzing, but before being combined with the water soluable ferric salt, the dextran is purified by one or more membrane processes having a cut-off value above 2,700 Daltons, optionally followed by further hydrolysis and followed by one or more membrane processes having a cut-off value of 340-800 Daltons. 3. The process of claim 2, characterized in the following step: preparing an aqueous solution, comprising resulting hydrogenated dextran and at least one water soluble ferric salt, adjusting the pH of said aqueous solution to a value above 10 by addition of a base; heating the mixture a temperature above 100 degree C. until it turns into a black or dark brown colloidal solution and filterable through a 0.45 mum filter; and purification and stabilization of the solution using filtration, heating and membrane processes and addition one or more stabilizers, and, optionally drying the solution to obtain the desired iron-dextran as a stable powder. 4. The process of claim 2, characterized in that the hydrogenation of the dextran is performed by means of sodium borohydride in aqueous solution. 5. The process of claim 3, characterized in that the stabilization comprises addition of at least one salt of an organic hydroxyacid, preferably selected from citrates. 6. Use of a compound, comprising hydrogenated dextran having a weight average molecular weight (Mw) of 700-1,400 Daltons, preferably approximately 1,000 Daltons, a number average molecular weight (Mn) of 400-1,400 Daltons, wherein 90% by weight of the dextran has a molecular weight of less than 2,700 Daltons and the Mw of the 10% by weight fraction of the dextran having the highest molecular weights is below 3,200 Daltons, said hydrogenated dextran having been subjected to purification by membrane processes having a cut-off value of 340-800 Daltons, in stable association with ferric oxyhydroxide for the preparation of parenterally administrable therapeutical composition for prophylaxis or treatment of iron-deficiency anemia in animal or human subjects. 7. A dextran compound, comprising a hydrogenated dextran having a weight average molecular weight (Mw) of 700-1,400 Daltons, preferably approximately 1,000 Daltons, a number average molecular weight (Mn) of 400-1,400 Daltons, wherein 90% by weight of the dextran has a molecular weight of less than 2,700 Daltons and the Mw of the 10% by weight fraction of the dextran having the highest molecular weights is below 3,200 Daltons, said hydrogenated dextran having been subjected to purification by membrane processes having a cut-off value of 340-800 Daltons. 8. A process for preparing a dextran compound of claim 7, in which the molecular weight of dextran is reduced by hydrolysis and the dextran is hydrogenated to convert functional aldehyde terminal groups into alcohol groups, characterized in that after the hydrolysis the dextran is purified by one or more membrane processes having a cut-off value suitable for holding back dextran of molecular weight above 2,700 Daltons, possibly followed by further hydrolysis and followed by one or more membranes having a cut-off value of 340-800 Daltons. 9. Use of a dextran product of claim 7 to produce iron-dextran compound. 10. A process for producing an injection liquid containing a compound of claim 1, characterized in dissolving the compound as a dry powder in an aqueous medium, adjusting the pH, if necessary, optionally adding stabilizer, and sterilizing the liquid by filtration before filling into ampoules or vials or by autoclave treatment after filling into such ampoules or vials. 11. A process for producing an injection liquid containing a compound of claim 1, characterized in that a liquid, comprising said compound, is purified, adjusted as to iron content and th pH value, stabilized and sterilized by filtration before being filled into ampoules or vials or by autoclave treatment after being filled into ampoules or vials.